Methods of preventing or treating diseases and conditions using complex carbohydrates

ABSTRACT

The invention relates to a method of preventing and treating diseases and conditions associated with allergies, autoimmunity, the adhesion cascade, the metastatic cascade or the coronary cascade comprising administering (i) at least one complex carbohydrate as the sole active ingredient, or (ii) at least one pharmaceutical composition which comprises as an active ingredient a pharmacologically effective amount of at least one low purity or cosmetic grade complex carbohydrate selected from the group consisting of oligosaccharides, sialylated oligosaccharides, polysaccharides and glycosaminoglycans, and an effective amount of at least one transdermal or transmucosal carrier in an amount effective to deliver the complex carbohydrate into the blood stream.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a Divisional Application of co-pending applicationSer. No. 10/343,240 filed on Jan. 30, 2003, and application Ser. No.10/343,240 is the national phase of PCT International Application No.PCT/US01/41473 filed on Jul. 31, 2000 under 35 U.S.C. §371, and PCTInternational Application No. PCT/US01/41473 claims priority under 35U.S.C. 119 of Provisional Application 60/222,046 filed Jul. 31, 2000.The entire contents of each is herein incorporated by reference.

FIELD OF THE INVENTION

The invention relates to novel uses for a composition of mattercomprising complex carbohydrates preferably as the sole activeingredient, applied topically, orally, mucosally or parenterally toprevent or treat diseases and conditions associated with allergies orthe adhesion, metastatic or coronary cascades. Also disclosed aremethods of preventing and treating the above-mentioned diseases andconditions by administering the complex carbohydrates of the presentinvention. Additionally, this invention describes novel uses for acomposition of matter comprising at least one complex carbohydrate andat least one transdermal or transmucosal carrier useful for effectingtransdermal or transmucosal migration resulting in topical or mucosaldelivery of macromolecules, through the skin or mucous membranes ofmammals and into the bloodstream. Methods of preventing diseases andconditions of mammals associated with allergies, autoimmune mechanisms,the adhesion cascade, the metastatic cascade and the coronary cascadeare also described wherein the combination of complex carbohydrates withessential oils is applied topically, orally, mucosally or parenterallyon a repeated basis until treatment is complete.

BACKGROUND OF THE INVENTION

For purposes of this invention, complex carbohydrates are defined as anypolymer comprising more than two sugar moieties and include such classesof compounds as polysaccharides and oligosaccharides. Polysaccharidesinclude mucopolysaccharides and mannans whereas oligosaccharides arecomprised of branched polysaccharides such as sialylated sugarsincluding milk sugars. The key milk sugars (also called hexaoses)incorporated in the general class of complex carbohydrates aredifucosyllacto-N-hexaose a and b, Disialyl-monofucosyllacto-N-hexaoseand monofucosyllacto-N-hexsaose I, II, and II (obtainable from OxfordGlycosystems, Inc.).

One of the most active areas of research at present is the study of thegenetics and function of mucopolysaccharides. These areglycosaminoglycans that can be obtained from numerous sources {e.g.rooster combs, trachea, umbilical cords, skin, articular fluids andcertain bacteria such as Streptococci spp). Most glycosaminoglycans(hyaluronic acid, chondroitin sulfates A, B, and C, heparin sulfate,heparin, keratan sulfate, dermatan sulfate, etc.) are composed ofrepeating sugars such as n-acetylglucosamine, glucuronic acid andn-acetyl galactosamine (these are known as non-sulfatedglycosaminoglycans). If such glycosaminoglycans contain sulfur groupsthey are known as sulfated glycosaminoglycans.

Heparin, hyaluronic acid and chondroitin sulfate are the most studiedmucopolysaccharides. Heparin has been used for a number of years as ananticoagulant. Hyaluronic acid has been used therapeutically since the1970s as a replacement for the vitreous humor of the eye post surgeryand, more recently, as replacement for joint fluid in arthritic joints.The mode of action for hyaluronic acid injected directly into joints fortreatment of arthritis has been proposed to be lubrication andreplacement of the degraded joint fluid with highly viscous hyaluronicacid. High molecular weight (>750,000 daltons) and high viscosity havebeen reported to be critical for this use. (For purposes of this patent,all molecular weights are expressed as daltons. The unit designationwill not be added hereinafter.)

In the 1980s, it was discovered that chondroitin sulfate, orpolysulfated glycosaminoglycan (known by its commercial name asADEQUAN®) could be injected intramuscularly for reduction of pain andinflammation associated with arthrosis of horses. The mechanism ofaction of this glycosaminoglycan has been speculated to be inhibition ofcertain degradative enzymes present in the joint fluid that areup-regulated by trauma.

In the 1990s, chondroitin sulfate had developed into a popularnutritional supplement being used extensively to treat joint problems.Such treatment requires oral doses between 1000 and 3000 mg/day forhumans. Even with these high doses (>15 mg/Kg), relief from joint painoften takes 6-9 months.

In 1989, it was discovered that intravenous, intramuscular orsubcutaneous delivery of hyaluronic acid could reduce the pain ofarthritis (U.S. Pat. No. 4,808,576 by Schultz et al) when the hyaluronicacid was delivered remote to the site of the arthritis (not into thejoint). This Schultz et. al. patent specifically states that thehyaluronic acid must be of high purity (>99% pure hyaluronic acid). Nomention is made of use of other complex carbohydrates,mucopolysaccharides or glycosaminoglycans administered by any method, oruse of hyaluronate sodium orally or mucosally, use of low purityglycosaminoglycans or treatment of other diseases or conditions byparenteral administration.

The importance of high molecular weight for effectiveness of hyaluronicacid in the treatment of arthritis is generally emphasized (see forexample Balazs, U.S. Pat. No. 4,141,973 and Howard and Mcllraith, TheCompendium, 15(3), March 1993) who summarize several clinical studiesconducted to determine the most efficacious molecular weight range ofhyaluronic acid injected intra-articularly to treat traumatic arthritisin horses. The conclusion from these studies was that hyaluronic acidwith a molecular weight below 1×10⁶ was not as effective as hyaluronicacid with a molecular weight above this value.

The most recent studies on hyaluronic acid discuss treatment of varioustypes of cancer with very large doses of this macromolecule (Falk, WO97/40841). This Falk application suggests that doses should exceed 750mg per 70 Kg person, preferably, exceeding 1 g per 70 Kg person. Thisdose level calculates to be approximately 10-20 mg/Kg. Such doses aregiven intermittently post diagnosis and are not suggested to bepreventative or administered in continuous low doses. Additionally, itis clear that the sodium hyaluronate of the Falk invention needs to bepure enough for injection even though oral administration is used inaddition to intravenous injection. In all cases, patients were treatedwith hyaluronan in addition to chemotherapy. Hyaluronan was not used asthe sole active ingredient for treatment of the cancer patients by Falk.

The adhesion cascade was first described in the early 1990s. In asummary by Adams and Shaw (The Lancet, 343, Apr. 2, 1994) the adhesioncascade is supposed to describe the mechanism by which pain and swellingare produced post trauma. It is divided into four sequential steps oftethering, triggering, strong adhesion and motility. Tetheringinteractions are mediated by a family of three lectin-likecarbohydrate-binding molecules (selectins). These interactions arestrong enough to cause the leukocytes to roll along the blood vesselwalls to the site of trauma instead of flowing freely through suchvessels as they would in a non-traumatized state. The triggeringresponse is stimulated by factors such as cytokines stimulated by atraumatic event and mediated by adhesion molecules called integrins.Integrins, by themselves, do not bind well to epithelium. However, whenactivated, integrins promote strong adhesion of the leukocyte to theepithelial surface. Leukocytes bind to the epithelial cells via theirreceptor sites such as CD44, CD31, etc. By a mechanism of attachment anddetachment the leukocytes are guided to the site of trauma. At the siteof trauma the adhesion to the blood vessel wall becomes stronger and theinteraction of these integrins with their ligands on the surface of theleukocytes are responsible for cessation of movement and flattening ofthe leukocyte. Finally, a process involving VCAM-1 and LFA-1 and othersuch integrins allows leukocytes to pass between endothelial celljunctions and into the tissue that has been traumatized. Collection ofleukocytes at the site of trauma produces inflammation which is thenfollowed by pain or other sequelae.

The metastatic cascade is very similar to the adhesion cascade. It hasbeen proposed that tumor cells of all types contain CD44 receptor siteson their surface. These CD44 receptor sites appear to be involved inmetastasis functioning similar to the receptor sites on leukocytes □tethering the tumor cells to the blood vessel wall and providing themotility necessary for movement from one site to another in themammalian body. A significant portion of the literature on CD44 andtumor cells/cancer teaches that hyaluronic acid or hyaluronan actuallystimulates metastasis (Eur. J. Cancer, 1999, March; 35 (3), 473-480).

A coronary cascade has recently been described in the Harvard HealthLetter (December 1999, pg. 4-5) and SCIENCE vol:285, 23 Jul., 1999, pg595-599). This cascade describes a new mechanism to explain thedevelopment of heart disease and stroke. Rather than the traditionaltheory that plaques are formed by a collection of cholesterol alone, thenew theory is based on the premise that there are stable and unstableplaques produced on blood vessel walls. Unstable plaques are the problemplaques because they are “swarming with T cells and macrophages” thatare responding to a site of trauma and triggering the adhesion cascaderesulting in inflammation. It is the “swarming T cells and macrophages”that make these plaques unstable. The T cells are described as sendingmacrophages a signal to release a protein called tissue factor which“spills out and encounters circulating blood, attracting platelets andtriggering formation of a clot that quickly blocks up the artery”.

Accordingly, it is totally unexpected that complex carbohydrates of thepresent invention could be administered topically, orally, mucosally orparenterally, in low doses, to prevent and treat diseases and conditionsassociated with allergies, the adhesion cascade, the metastatic cascadeand the coronary cascade described herein.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph demonstrating the effect of treating an adultsuffering with Attention Deficit Disorder with various formulations ofhyaluronic acid.

FIG. 2 is a graph demonstrating the effect of treating a 9 year oldchild suffering from Attention Deficit Hyperactivity Disorder withhyaluronic acid.

SUMMARY OF THE INVENTION

The present invention relates to a method of preventing and treatingdiseases and conditions associated with allergies, autoimmunity, theadhesion cascade, the metastatic cascade or the coronary cascadecomprising administering (i) at least one complex carbohydrate as thesole active ingredient, or (ii) at least one pharmaceutical compositionwhich comprises as an active ingredient a pharmacologically effectiveamount of at least one low purity or cosmetic grade complex carbohydrateselected from the group consisting of oligosaccharides, sialylatedoligosaccharides, polysaccharides and glycosaminoglycans, and aneffective amount of at least one transdermal or transmucosal carrier(e.g. essential oil) in an amount effective to deliver the complexcarbohydrate into the blood stream.

Accordingly, the present invention relates to using complexcarbohydrates, including but not limited to mucopolysaccharides andglycosaminoglycans, to bind to the receptor sites on leukocytes (e.g.CD44 and CD31) blocking their ability to tether to the blood vesselwalls, inhibiting the motility to the site of trauma thus reducing thepain, swelling and other sequelae associated therewith (interrupting theadhesion cascade). Additionally, the present invention teaches thatcomplex carbohydrate molecules, including but not limited tomucopolysaccharides and glycosaminoglycans, bind to the receptor siteson tumor cells blocking their ability to tether to the blood vesselwalls and inhibit the tumor motility which, in turn, inhibits thepotential for metastasis.

The compositions of the present invention inhibit the macrophages fromswarming to a site of irritation or trauma on a blood vessel wallwherein said macrophages would normally accumulate producing theunstable plaques described previously, thus preventing and treatingheart disease and stroke. Additionally, the compositions of the presentinvention inhibit the T-cell and macrophage “swarming” thus blocking therelease of the tissue factor (referred to previously) and preventingcardiac events caused by said ruptured plaques.

In another embodiment of the present invention allergies andallergy-related diseases, diseases associated with the bodies' adversereactions to stimuli such as foods, inhalants and drugs wherein saidadverse reactions include but not limited to Attention Deficit Disease,Attention Deficit Hyperactivity Disease, interstitial cystitis, autism,migraines, asthma, Turret's Syndrome, fibromyalgia, anaphylaxis,rhinitis, sinusitis and inflammation providing the environment for yeastinfections, bacterial infections or virus infections and autoimmunediseases wherein the bodies' macrophages attack its own body tissues andorgans producing diseases including but not limited to rheumatoid andosteoarthritis, Lupus Erythematosis, multiple sclerosis, polymyositis,muscular dystrophy, Diabetes, and potentially Alzheimer's Disease, areassociated by a mechanism similar to the adhesion cascade. Therefore,CD44, CD31, RHAMM and other similar receptors are involved in producingthe allergic reaction and the autoimmune response. Again, the binding ofcomplex carbohydrates to these receptor sites inhibit the reactionand/or response. Therefore, allergies, allergy-related diseases andautoimmune diseases respond to treatment by oral, mucosal, topical andparenteral administration of complex carbohydrates as described herein.

One of the most recent theories to explain the significant neurologicaldegeneration that occurs in Alzheimer's Disease involves a substantialinflammatory component (SCIENCE, vol: 286, 17 Dec., 1999, pgs 2352-2355)which is concluded herein to be related to the adhesion cascade.Therefore, the present inventors have found that the complexcarbohydrates of this invention can be used to prevent and/or treatAlzheimer's Disease. Another explanation for the development of dementiaand Alzheimer's Disease is that an amyloid protein is produced in thebrain resulting in the formation of amyloid plaques that lead toneuronal degeneration. The neuronal degradation is associated withdiseases related to various types of dementia including but not limitedto Alzheimer's Disease. Since it is known that CD44 is present insignificant amounts on neuronal cells in the brain, the complexcarbohydrates of the present invention bind to CD44 and/or otherreceptor sites in the brain and inhibit the formation of such amyloidplaques.

Accordingly, although not bound by any theory, the invention relates toa composition of matter comprising complex carbohydrates preferably asthe sole active ingredient, applied topically, orally, mucosally orparenterally to prevent and treat diseases and conditions associatedwith allergies, autoimmunity, and the adhesion, metastatic or coronarycascades. However, the compositions described in U.S. Pat. No. 5,888,984and in PCT/US00/02328 may also be utilized in the methods of the presentinvention.

Additionally, this invention describes a composition of mattercomprising at least one complex carbohydrate and at least onetransdermal or transmucosal carrier useful for effecting transdermal ortransmucosal migration of said complex carbohydrate, resulting intopical or mucosal delivery of said molecules, through the skin ormucous membranes of mammals and into the bloodstream in order to preventor treat the diseases and conditions associated with allergic reactions,the adhesion cascade the metastatic cascade or the coronary cascade.Transdermal carriers are those compounds that allow molecules, includingmacromolecules to pass through the skin and into the blood stream ofmammals. Transmucosal carriers are those compounds that allow moleculesincluding macromolecules to pass through the mucous membranes and intothe blood stream of mammals. A patch or bandage can be embedded with thecomplex carbohydrates of the present invention so as to extend deliveryof the molecules and/or provide slow release over several days. In theuse of the complex carbohydrates of the present invention in bandages,they can be used without the presence of transdermal or transmucosalcarriers with open wounds, or containing said carriers when used totreat closed wounds or reduce scarring or scar tissue.

This invention further describes a method of preventing and treatingdiseases and conditions of mammals associated with allergies,autoimmunity, the adhesion cascade, the metastatic cascade or thecoronary cascade comprising administering a composition of complexcarbohydrates topically, orally, mucosally or parenterally preferably ona repeated basis (e.g. 2 times per day, preferably 4 times per day, andmost preferably 8 times per day, or simply “as needed”).

Applications of the present invention would be made on a repeated basisfor the term of the disease or condition or as long as necessary toprevent the diseases or condition from progressing, or to treat thediseases or conditions until they are resolved.

Finally, this invention describes a mechanism by which inflammation,including diseases and conditions associated therewith, tumor growth,tumor metastasis, allergies and allergy-related diseases, autoimmunediseases, coronary diseases and central nervous system diseases can beprevented or treated by administering complex carbohydrates topically,orally, mucosally, or parenterally.

It is understood that this invention describes the prevention andtreatment of numerous diseases and conditions including but not limitedto arthritis (osteoarthritis and rheumatoid arthritis), gastritis,stomach or intestinal ulcers, colitis, esophagitis, bronchitis, thecommon cold, rhinitis, sore throat, tonsillitis, tendonitis,fibromyalgia, chronic fatigue syndrome, interstitial cystitis,polymyositis, autism, Lupus Erythematosis, headaches includingmigraines, pancreatitis, anaphylaxis, vaginitis, hemorrhoids, sunburn,heat burns, temporomandibular joint (TMJ) condition, gingivitis, dentalcaries, dental pain, post surgical pain, menstrual pain, extremitycramps, pre and post partum pain, itching associated with allergies andhypersensitivity (e.g. poison ivy, oak and sumac and eczema), asthma,emphysema, Attention Deficit Disorder, Attention Deficit HyperactivityDisorder (ADHD), fibromyalgia, Turret's Syndrome, Multiple Sclerosis,Amyotrophic Lateral Sclerosis (ALS) or Lou Gehrig's Disease, Parkinson'sDisease, high blood pressure, heart disease, heart attack, vasculitis,stroke, increased degradation of spinal nerves post spinal cord injury,head or brain trauma post injury, adhesion formation post surgery orchemotherapy, scar formation post surgery, non-healing wounds, decubutisulcers, irritation of nerve bundles (e.g. trigger points) ganglionformation, dementia including but not limited to Alzheimer's disease,Human Immunodeficiency Virus infection (HIV), yeast infections,bacterial infections, viral infections, encephalitis, epilepsy,meningitis, peripheral neuropathy, Creurtfeldt-Jacob Disease, Bell'sPalsy, cognitive disorder, cancer, Diabetes, skin problems such as acne,lick granulomas, hot spots, psoriasis, rashes, wrinkles, and even hairloss.

Such prevention and treatment are accomplished by topically, orally,mucosally or parenterally applying complex carbohydrates of the presentinvention to mammals in an amount and number of applications so as to beeffective in preventing and treating the target disease or condition. Itis understood that such prevention or treatment results in blockage ofreceptor sites associated with allergies, autoimmune mechanisms, theadhesion cascade, metastatic cascade, or coronary cascade.

DETAILED DESCRIPTION OF THE INVENTION

This invention describes novel uses for a composition of mattercomprising at least one complex carbohydrate that is applied topically,orally, mucosally or parenterally to prevent and/or treat diseases andconditions associated with allergies, autoimmunity, the adhesioncascade, the metastatic cascade or the coronary cascade. The inventionalso encompasses novel uses for a composition comprising at least onecomplex carbohydrate and at least one transdermal or transmucosalcarrier. The invention also preferably encompasses novel uses for acomposition of matter comprising complex carbohydrates as the soleactive ingredient. Further, the compositions disclosed in U.S. Pat. No.5,888,984 and in PCT/US00/02328 (including provisional applications60/117,988 filed Feb. 1, 1999, 60/127,749 filed Apr. 6, 1999, 60/137,098filed Jun. 2, 1999, 60/142,306 filed Jul. 3, 1999 and 60/166,326 filedNov. 19, 1999 on which priority is based in PCT/US00/02328) may also beutilized in the methods of the present invention.

More specifically, the present invention is directed to a method ofpreventing and treating diseases and conditions associated withallergies, autoimmunity, the adhesion cascade, the metastatic cascadeand the coronary cascade comprising administering said complexcarbohydrates to the affected mammal topically, orally, mucosally orparenterally. A significant feature of this invention is that thecomplex carbohydrates are preferably administered in a low dose. By lowdose is meant from 0.000001 mg/kg to 150 mg/kg, preferably from 0.001mg/kg to 100 mg/kg and more preferably from 0.01 mg/kg to 20 mg/kg.

The invention also describes a method for reducing the sequelae oftrauma in irritated or inflamed tissue of mammals by the topical ormucosal application of a mixture of a transdermal or transmucosalcarrier and one or more complex carbohydrates or mixtures thereof. Thecomposition described is applied directly on or over the traumatizedsite or on a mucous membrane.

Finally, the invention describes a method for reducing the sequelae oftrauma in irritated or inflamed tissue of mammals by topical, oral,mucosal or parenteral application of a complex carbohydrate of thepresent invention or mixture thereof as the only active ingredient. Bytrauma is meant an event that produces an adverse effect on a mammal. Bysequelae of trauma is meant the pain, swelling, inflammation, adhesionformation, nerve damage, nerve sensitivity and any other physiologicalchange that results from trauma.

Many of the complex carbohydrates of the present invention aremacromolecules. Macromolecules as used herein means any molecule with amolecular weight >1000 daltons (Da). Mammals as used herein includes butis not limited to humans, dogs, cats, horses, cattle, swine, rabbits,guinea pigs, mice. Topical administration as used herein meansapplication to the dermis anywhere on the mammal, including into the earcanal. Mucosal administration as used herein means application to anymucous membrane of a mammal. Mucous membranes include but are notlimited to the mouth, gums, nasal passage, throat, vagina and therectum. Transdermal as used herein means transfer of molecules,including macromolecules through the skin of mammals so that the complexcarbohydrates may act systemically. Transmucosal as used herein meanstransfer of molecules, including macromolecules through the mucousmembranes of mammals so that the complex carbohydrates may actsystemically.

Diseases preventable and treatable by the present invention include butare not limited to tonsillitis, the common cold, pancreatitis,ulcerative colitis, stomach or intestinal ulcers, cold sores, LupusErythematosis, Parkinson's Disease, osteoarthritis, degenerativearthritis, rheumatoid arthritis, polymyositis, Amyotrophic LateralSclerosis (ALS) or Lou Gehrig's Disease, multiple sclerosis,Creutzfeldt-Jakob Disease heart disease, heart attack, vasculitis,stroke, Alzheimer's disease, asthma, emphysema, allergy-relateddiseases, Human Immunodeficiency Virus (HIV) disease, yeast infections,bacterial infections, encephalitis, epilepsy, meningitis, peripheralneuropathy, Bell's Palsey, Cerebral Palsey, cancer and Diabetes.Conditions preventable and treatable by the above-described complexcarbohydrates include but are not limited to ulcers, gastritis,esophagitis, bronchitis, sore throat, tendonitis, fibromyalgia,headaches including migraines, vaginitis, anaphylaxis, hemorrhoids,sunburn, heat burns, temporomandibular joint (TMJ) conditidn, dentalcaries, dental pain, gingivitis, post surgical pain, menstrual pain,cramps, pre and post partum pain, interstitial cystitis, itchingassociated with allergies and hypersensitivity (poison ivy), painassociated with insect bites or stings, Attention Deficit Disorder,Attention Deficit Hyperactivity Disorder (ADHD), Turret's Syndrome,plaque formation in arteries and veins, degradation of spinal nervespost spinal cord injury, head and brain trauma post injury, adhesionformation post surgery or post chemotherapy treatments, scar formationpost surgery, wound healing, decubutis ulcers, irritation of nervebundles (trigger points) ganglion formation, cognitive disorder, skinproblems such as acne, eczema, lick granulomas, hot spots, psoriasis,rashes, wrinkles, and even hair loss.

Particularly amenable conditions or diseases targeted for suchprevention or treatment include but are not limited to irritated orinflamed muscles, cramped muscles, inflamed tendons, inflamed nerves ornerve bundles (e.g. inflamed ganglion, lick granulomas, trigger points,fibromyalgia), swollen and painful joints, inflamed bladder(interstitial cystitis) bruised tissue, tired feet, allergic conditionsof the skin, other allergic conditions (e.g. hot spots, psoriasis,asthma, ADD and ADHD), chronic fatigue syndrome, open wounds, decubitisulcers, burns, sunburns, inflamed stomach or intestinal lining(gastritis, colitis, ulcers), dental problems, inflamed bronchi oresophagial lining, adhesions formed after surgery, trauma orchemotherapy, pain post surgery, dental work or injury, plaques formedon veins or arteries leading to heart disease and stroke, inflammationassociated with Alzheimer's Disease, Multiple Sclerosis, amylotropiclateral sclerosis (ALS), head or brain trauma, degration of the spinalcord post spinal cord injury, tumor formation and tumor metastasis.

A significant advantage of this invention is that pharmaceutical gradecomplex carbohydrates are not required for topical, oral or mucosalapplication. The invention preferably uses cosmetic or food grade (e.g.low purity) complex carbohydrates for these applications. Such complexcarbohydrates can be obtained from any source as long as the source isnot contaminated with undesirable adventitious agents (disease-producingviruses, bacteria, fungi, parasites, etc.). Such low purity complexcarbohydrates such as mucopolysaccharides may be contaminated with up to20% wt/vol proteins, 15% wt/vol nucleic acids, 1% wt/vol teichoic acids,5% wt/vol lipids, fractions of hyaluronic acid <30,000 (defined asreactive by both Balazs in U.S. Pat. No. 4,141,973 and della Valle inU.S. Pat. No. 5,166,331), 5% wt/vol endotoxins and other smallmolecules. They will cause reactions when injected into monkey eyes orjoints of horses but will not cause reactions when applied to the skinof mammals or when delivered orally or mucosally to such mammals.Because the low purity pharmaceutical compositions of this invention areapplied topically, orally or mucosally, these contaminants produce noadverse reactions (e.g. irritation or blistering of skin). Additionally,if one must select and use only certain molecular weight ranges ofhyaluronic acid or salts thereof, the cost would be prohibitive. Infact, the presence of multiple molecular weight fractions incompositions of the immediate invention is preferable for efficacy.

In order to assure freedom from contaminating microorganisms, theformulations of this invention can include preservatives allowable infoods or topical preparations. Allowable preservatives include but arenot limited to methyl and propyl parabens, propylene glycol,ethylenediamine tetraacetic acid (EDTA), sorbitol, ascorbic acid,sorbate and sorbic acid, benzoic acid, and any other acceptablepreservative, including mixtures thereof.

All molecular weight ranges of complex carbohydrates are effective informulations of this invention. For instance, complex carbohydrates witha molecular weight of <1,000, 1,000 to 30,000,100,000-500,000, >1,000,000 or >4,000,000 have proven to be effective.It has been found that complex carbohydrates, especiallyglycosaminoglycans with lower molecular weights (e.g. <30,000) act morequickly than those with high molecular weights (e.g. >1,000,000).Indeed, for treatment of allergy-related diseases and autoimmunediseases or conditions, it is preferable to administerglycosaminoglycans, especially sodium hyaluronate, salts or derivativesthereof (also called hyaluronic acid or hyaluronan) with a molecularweight average below 300,000 Da. For inflammatory diseases, diseases orconditions related to the adhesion cascade, the metastatic cascade orthe coronary cascade, the high molecular weight glycosaminoglycansprovide a longer-lasting effect. The latter macromolecules are brokendown by enzymes in the body (hyaluronidase) to smaller molecules thatare active in binding or stimulate production of increased amounts oflower molecular weight hyaluronic acid by the mammals' own body.Therefore, there is a longer release of the more active smallermolecules producing a longer period of efficacy. Thus, the preferredformulation for most treatments includes a mixture of low and highmolecular weight complex carbohydrates.

It has been noted by the inventors that the optimum molecular weight fortreatment of allergies, allergy-related diseases and conditions, asthma,ADD and ADHD is between 30,000 and 500,000 Da, preferably between100,000 and 300,000. It has been determined that very high molecularweight (>4×10⁶) is essentially ineffective for treatment of the above.

The complex carbohydrates useful in combination with transdermal ortransmucosal carriers for direct topical or mucosal application on sitesof trauma or to be absorbed therein, may be of any type alreadyrecognized as useful for parenteral treatment. Additionally, complexcarbohydrates, including polysaccharides, glycosaminoglycans or theirderivatives that bind to leukocyte receptor sites and/or bind toselectins, integrins, or any other receptor sites that are involved withthe mechanisms by which leukocytes move to sites of trauma or thatenable metastasis of tumors and that, when bound, serve to inhibit anyof the steps of the adhesion cascade, allergy or autoimmune mechanisms,the metastatic cascade, or the coronary cascade would be useful in suchpharmaceutical compositions. Such compounds may be obtained from anysource. They can be extracted from rooster combs (U.S. Pat. No.4,141,973), produced by fermentation of bacteria (U.S. Pat. No.4,782,046), or extracted from trachea, skin, umbilical cords, etc. andneed only be pure enough to be used as a cosmetic in that they do notcause reactions when administered topically, orally or mucosally. Thesemolecules include but are not limited to polysaccharides,glycosaminoglycans such as hyaluronic acids and derivatives or saltsthereof (Genzyme, Lifecore Biomedicals, Meiji Seika Kaisha, Ltd.),chondroitin sulfates A, B, or C or their derivatives (SIGMA ChemicalCompany), keratan sulfate and derivatives thereof (SIGMA ChemicalCompany), heparin or heparin sulfate and derivatives thereof (SIGMAChemical Company, Rhone Poulenc Rorer Pharmaceuticals), dermatan sulfateand derivatives thereof (SIGMA Chemical Company) and certain sialylatedsugars such as trifucosyllacto-N-hexaose and sialyl Lewis^(x) (OxfordGlycosystems). The sources listed are exemplary only and not limitationsof the invention.

The preferred complex carbohydrates of this invention aremucopolysaccharides (glycosaminoglycans) including hyaluronic acid andsalts, sulfates or derivatives thereof, chondroitin sulfate andpolysulfated forms, salts or derivatives thereof, sialyl Lewis^(x) andsalts or derivatives thereof, heparin and sulfates, salts or derivativesthereof, dermatan, and sulfates, salts or derivatives thereof, keratinand salts, sulfates and derivatives thereof, as well as combinations ofthe above. The most preferred complex carbohydrates are hyaluronic acidincluding salts, sulfates or derivatives thereof, chondroitin sulfateincluding polysulfated forms, low molecular weight heparin includingsalts, sulfates and derivatives thereof and sialyl Lewis^(x) includingsalts and derivatives thereof and combinations thereof.

It is a preferred embodiment of this invention that at least twodifferent molecular weight ranges of complex carbohydrates be includedin the composition. At least one should be from a low molecular weightrange {from 1000 to <50,000 (e.g. 49,000)} and the other one or moreshould be from a higher molecular weight range (from 100,000 to 500,000or >1,000,000). Such complex carbohydrates may or may not be a mixtureof two or more different types of complex carbohydrates. For instance,one complex carbohydrate providing the high molecular weight moietycould be selected from the group consisting of glycosaminoglycans suchas hyaluronic acid and another complex carbohydrate in the samepharmaceutical composition providing the low molecular weight moietycould be a second polysaccharide or a sialylated sugar selected from thegroup consisting of chondroitin sulfate, keratan sulfate, heparin,heparin sulfate, dermatan sulfate, acemannan, sialyl Lewis^(x), andhexaoses. When heparin is used, it is advantageous to use low molecularweight heparin as it has been demonstrated to be free of anti-coagulantactivity. However, high molecular weight heparin will be broken down tolow molecular weight heparin when administered orally or mucosally.

A more preferred embodiment of this invention comprises a mixture of atleast two glycosaminoglycans. One of the glycosaminoglycans would be ofa low molecular weight range (<30,000). The second glycosaminoglycanwould be of a high molecular weight (>500,000 Da).

The most preferred embodiment of this invention comprises a mixture oftwo or more molecular weight ranges of hyaluronic acid or salts orderivatives thereof, such as sulfates, acetates, phosphates, methylatesand nitrates. Said composition comprises for instance, a hyaluronic acidor salt or derivative thereof with a molecular weight of <100,000 Dacombined with a hyaluronic acid or salt or derivative thereof which hasa molecular weight >1,000,000 Da.

Routes of administration of the complex carbohydrates of the presentinvention include parenteral (discussed below), topical whereby thecompounds may or may not be combined with transdermal carriers includingbut not limited to essential oils; oral whereby the compounds may or maynot be mixed with transmucosal carriers including but not limited toessential oils or other transmucosal carriers, coated with protectiveoral delivery materials such as hydrogels, carbopols, etc., or deliveredorally without a coating wherein the complex carbohydrates are the soleactive ingredient, mucosally wherein the complex carbohydrates are thesole active ingredients or parenterally. For purposes of this invention,mucosal delivery includes but is not limited to application of thecompounds to the mucous membranes of the nose, eyes, mouth, throat,gums, tonsils, eyes, esophagus, stomach, colon, rectum, vagina, or anyother mucous membrane.

It should be understood that complex carbohydrates used for parenteraladministration to mammals must be pure enough to be injected safelywithout causing adverse local or systemic effects and of a viscosityallowing ease of injection. The preferred viscosity is that which issafe to administer without stimulating an adverse effect in a mammal.The intravenous route would require a lower viscosity than otherparenteral routes of administration. For instance, a viscosity of 500centipois should not cause problems. A preferred viscosity is less than200 centipois. In the case of parenteral injections, especially thoseadministered IV, pharmaceutical grade complex carbohydrates may benecessary. Parenteral injections may be administered intramuscularly(IM), intravenously IV), subcutaneously (SC), intradermally (ID),intraparitoneally (IP) and/or injected into tumors.

The parenteral formulation of the present invention may be in an aqueousform as a liquid or gel that is safe when injected IM, SC, IV, ID, IP,or by any other route of administration. This formulation must be purerand be of a pharmaceutical grade. By a pharmaceutical grade is meantthat it should be sterile, contain <3% protein (w/w), <5 μg/mL nucleicacids as measured by UV absorbance at 260 nm, <0.5 EU/mL endotoxin asmeasured by LAL, <80 ppm (w/w) iron and <1.0 ppm heavy metals. The mosteffective injectable formulation would contain mucopolysaccharides orglycosaminoglycans, more specifically, low molecular weight heparin,hyaluronic acid of all molecular weights, chondroitin sulfate, dermatansulfate and/or keratin sulfate. If hyaluronic acid is used, theviscosity must be at a level acceptable to be injected by the routechosen without causing adverse reactions. For instance, high viscosityhyaluronic acid >1000 centipoise would not be injected intravenouslywhereas it could be injected subcutaneously or intramuscularly. Lowviscosity hyaluronic acid <500 centipoise could be injectedintravenously, subcutaneously or intramuscularly.

Administration of complex carbohydrates by the parenteral routes ofadministration has been found to be particularly effective in thetreatment of any type of inflammation, pain, nerve damage, nervesensitivity, autoimmunity and/or itching which is associated with theadhesion cascade, tumors associated with the metastatic cascade anddevelopment of heart diseases and stroke associated with the coronarycascade described earlier. This route of administration is preferablefor treatment of pain post surgery or dental procedures, treatment forvarious types of cancer wherein patients cannot ingest food or liquids,treatment of degenerative muscle and joint diseases including thetreatment of Multiple Sclerosis, ALS, osteoarthritis, rheumatoidarthritis, or post partum pain. It is also useful for treatment ofspinal cord injuries, treatment of heart attacks and stroke (e.g. heartdisease due to high blood pressure and stroke), treatment of pain andswelling and/or fractures resulting from athletic injuries, treatment ofinflammation and pain associated with bursitis, reduction ofinflammation (edema) in extremities resulting from diabetes, reductionof inflammation and pain in association with interstitial cystitis,treatment of decubitus ulcers resulting from poor circulation bydiabetic patients or bedridden patients, treatment of inflammation anditching of skin resulting from severe allergic reactions such as poisonivy and insect bites/stings, treatment of sever ADD, ADHD or autism,treatment of anaphylaxis, treatment of polymyositis, treatment ofinflammation and pain associated with tendonitis, treatment ofinflammatory skin conditions such as severe acne or psoriasis andtreatment of burns or sunburn. In severe situations, treatment mayinclude both parenteral injection and oral, mucosal or topicalapplication of one or more complex carbohydrates.

As indicated earlier, the most recent theories to explain heart attacksand stroke involves the eruption of unstable plaques which have beenfound to be infiltrated with T-cells and macrophages thus linking thesedisease syndromes to the adhesion cascade. Thus, the present inventorshave determined that heart disease (high blood pressure, heart attacksand stroke) can be treated with the complex carbohydrates of thisinvention. Further, hyaluronic acid, chondroitin sulfate, heparinsulfate, low molecular weight heparin, keratin sulfate or dermatansulfate, including salts or derivatives thereof can be taken daily as apreventative for heart disease and stroke. Preferably, amounts from 1mg/day to 20 mg/day are used to prevent heart disease and stroke. Thiscould be administered orally or mucosally. Acute disease, includingheart attacks could be treated by parenteral injection of the complexcarbohydrates of the present invention. Alternately, a mixture ofhyaluronic acid and chondroitin sulfate could be administered daily forprevention of heart disease and stroke. Again, the daily dose wouldpreferably be less than a total of 100 mg. Repeated low doses have beendemonstrated to be between 0.0001 mg and 100 mg.

For topical, oral and mucosal deliver, transdermal or transmucosalcarriers can be added to enhance the penetration of the complexcarbohydrates through the skin or mucous membranes. Transdermal andtransmucosal carriers include but are not limited to essential oils,polymer blends containing low density polyethylene copolymer or ethyleneand 1-butene, 1-hexene, or 1-octene and a linear low densitypolyethylene copolymer, chemical esters, salicylates, dimethyl sulfoxide(DMSO) and glycocholates. It is preferred that very low concentrationsof essential oils be used to orally or mucosally deliver the complexcarbohydrates of the present invention, including the macromolecules,through mucous membranes and, consequently, into the blood stream. Byvery low concentration of essential oils for use in mucosal orparenteral administration is meant that the essential oil is added to aconcentration in an amount from 0.00001% to no more than 1%, preferably,no more than 0.01%, more preferably no more than 0.005%. Therefore,concentrations of essential oils around 0.00001% and 0.005% arepreferred for transmucosal delivery.

Transdermal formulations of the present invention utilize slightlyhigher concentrations of essential oils. These range from 0.05% to 5.0%,preferably from 0.5% to 3.0%.

The essential oils of the present invention may be either natural orsynthetic and may be obtained from any source. For instance, naturalEucalyptus Oil, Rosemary Oil, Pine Needle Oil, Tea Tree Oil, Sage Oil,Jojoba Oil, Cinnamon Oil, Anise Oil, Lemon Oil, Lime Oil, Orange Oil,Peppermint Oil, Spearmint Oil, Wintergreen Oil, Clove Leaf Oil, AlmondOil, White Pine Oil, Camphor Oil, Cardamon Oil, Cedar Leaf Oil, SweetBirch Oil and many others can be purchased from Lorrann Oils. SyntheticWintergreen Oil, Anise Oil, Fir Tree Oil, Rose Oil and Camphor Oil canbe obtained from the same source. Menthol and derivatives thereof can beobtained from SIGMA Chemical Company. The purity of these essential oilsis of little concern as long as they meet the requirements for a food orcosmetic and do not produce adverse reactions when applied to the skinof mammals. An example of an animal-derived essential oil is EMU oil,extracted from the skin of the EMU.

The formulation of a complex carbohydrate with a natural or syntheticessential oil should be adequate to form an emulsion, suspension,solution, cream or ointment at the time of application. A liquidformulation will not be effective if the oil is separated from theaqueous phase. However, a suspension or solution that may be resuspendedby shaking prior to application is acceptable for use. Any cream orointment base that does not interfere with the effectiveness of theactive ingredients may be included in the formulation. Therefore, oneembodiment of this invention is a cream base containing at least onecomplex carbohydrate and at least one essential oil. Another embodimentis an ointment base containing at least one complex carbohydrate and atleast one essential oil. One preferred embodiment is a liquid or gelformulation in an aqueous base that contains at least one complexcarbohydrate and at least one essential oil. A significant advantage ofthis liquid formulation is that the preparation is not greasy or oily,does not leave a greasy or oily film on the skin and does not leave alingering odor on the skin. The most preferred embodiment is a liquid orgel formulation in an aqueous base that contains at least one complexcarbohydrate as the sole active ingredient.

The complex carbohydrates of the present invention can also be preparedas a solid and incorporated into bandages. Preferably a 1% solution isused. It can be embedded into the bandage material remaining moist, ordried. It can also be formulated into a solid polymer by addition ofcross-linking agents. The latter may be applied to open wounds or toscars to assist with the healing process and/or reduce scar formation.

The treatment of irritated or inflamed mammalian tissue by directtopical application requires a dose or total dose regimen effective toreduce or alleviate the results of the trauma. It is preferred toadminister at least about 0.000001 mg/Kg of body weight of eachingredient over the site of trauma at least once per day or as often asnecessary. The components of this formulation are naturally-occurringsubstances and are safe when applied topically. There is no inherentupper limit to the tolerable dose. However, as in all medicinaltreatments it is prudent to use no more than is necessary to achieve thedesired effect. It has been noted that more intense inflammation andpain require more dose applications for relief. A dose of 100 mg/Kg ofbody weight has been used safely and could serve as an upper limit foruse. Similar dose regimens are recommended for wound healing whereas thepharmaceutical composition is applied on the wound until adequatepromotion of granulation of the wound has occurred and healing iscomplete.

A convenient topical application formulation is a combination of one ormore complex carbohydrates such as polysaccharides, oligosaccharides, orglycosaminoglycans at a total concentration of between 0.1% and 5%wt/vol. These can be used without a transdermal carrier or with atransdermal carrier including one or more essential oils. If essentialoils are used, they are preferably combined with the complexcarbohydrates at a total concentration of between 0.5% and 20% vol/volwith the remainder of the formulation being made up of a liquid, creamor ointment base. The liquid base may be aqueous.

A preferred embodiment of the topical formulation is a combination ofone or more glycosaminoglycans at a total concentration of between 0.1%and 5% wt/vol with one or more essential oils at a total concentrationof between 0.5% and 5% vol/vol with the remainder of the formulationbeing a cream, ointment or aqueous base.

A more preferred embodiment of the invention is a combination of equalamounts of two or more molecular weight ranges of glycosaminoglycans(one below 30,000 and one above 500,000) at a combined concentration ofbetween 0.5% and 3.0% wt/vol with two or more essential oils having atotal concentration of between 0.5% and 5.0% vol/vol with the remainderof the formulation being an aqueous, cream or ointment base.

The most preferred embodiment of the topical formulation is acombination of hyaluronic acid (sodium hyaluronate or hyaluronan) with amolecular weight <30,000 with hyaluronic acid with a molecular weightbetween 100,000 and 500,000 or >750,000 at a total hyaluronic acidconcentration of between 0.5% and 3.0% wt/vol and an essential oilselected from the group comprising Rosemary Oil, Tea Tree Oil,Wintergreen Oil, Eucalyptus Oil, Menthol and Camphor at a concentrationof between 1.0% and 3.0% vol/vol with the remainder of the formulationbeing DI water.

Preferred complex carbohydrates include heparin, preferably lowmolecular weight, hyaluronic acid, chondroitin sulfate, dermatansulfate, keratan sulfate, and acemannan (active ingredient of AloeVera).

Preferred essential oils include Tea Tree Oil, Rosemary Oil, EucalyptusOil, Wintergreen Oil, Sage Oil, Jojoba Oil, White Pine Oil, Camphor Oil,Cinnamon oil, Oil of Clove, Spearmint Oil, Peppermint Oil, EMU Oil andMenthol.

The oral and mucosal formulations of the present invention include anyof the complex carbohydrates listed above, alone or in combinations,whereby the formulation is administered as a form selected from thegroup consisting of a liquid, an emulsion, a suspension, a cream, anointment, a gel, a foam, a spray, a solid, a powder and a gum. It iscontemplated that the liquid or solid could be added to a drink or drinkmix, to food, be a part of a soft drink or any other type of carbonateddrink, a supplement drink, used as a mouthwash, or added to a mouthwash,as a toothpaste, as a gargle, as a spray, added to a vaporizer, as aliquid center of a gum or throat lozenge, added to a food, cookie ortreat, or used in any other way so as to retain the effectiveness of thecomplex carbohydrate. A gel form can include a gel applied by mouth, tothe gums, to the tongue, under the tongue, to the eyes, to the nose, tothe vaginal area or vagina, or to the rectum. A foam could be added towounds, to the mouth, to the gums, to the vagina or any other mucousmembrane. A solid can be incorporated into food, treats such as candy ortreats for animals, a chewing gum, a dissolvable gum, a lozenge,capsules, tablets, dissolvable tablets, suppositories, a bandage and anyother form that would not damage the effectiveness of the complexcarbohydrates or the essential oils, if used in the formulation. Otheradditives may be added to said oral formulations to improve taste andpalatability or enhance the flavor. For instance, treats for horses mayinclude sugar, flavorings such as apple or peppermint or a liquid or gelmay be applied to a sugar cube, food or other treat. Treats for dogs mayinclude liver, apple, peppermint, yeast or any other palatableflavoring.

The same formulations as mentioned for oral use can be used for mucosaldelivery of the complex carbohydrates. The only limitation is that theformulation remain in contact with a mucosal surface for a period of atleast 2 to 10 seconds.

Although the complex carbohydrates may be added to foods that are thenbaked, it is preferred to add the complex carbohydrates to the surfaceof the food after baking is complete. This retains the greatestactivity.

It is contemplated that the complex carbohydrates of the presentinvention may be added to nutritional supplements to enhance theireffectiveness. For instance, a mixture of complex carbohydrates andzinc, zinc gluconate, zinc gluconate glycine could be used for moreeffective treatment of sore throat and colds. A mixture of the complexcarbohydrates of this invention and capsicum may produce an even moreeffective treatment for joint pain and swelling. Addition of vitamins,minerals and other nutritional additives may produce enhancement of thenutritional activity by the complex carbohydrates.

The most recent theory to explain the significant neurologicaldegeneration that occurs in Alzheimer's Disease involves a substantialinflammatory component (SCIENCE, vol: 286, 17 Dec., 1999, pgs 2352-2355)which appears to be related to the Adhesion cascade. Therefore, thepresent inventors have determined that the complex carbohydrates of thisinvention can be used to prevent and/or treat Alzheimer's Disease. Forexample, it is contemplated that hyaluronic acid, salts or derivativesthereof could be administered daily as a preventative for Alzheimer'sDisease. Amounts from 1 mg/day to 20 mg/day should prevent thedegradation apparent in Alzheimer's Disease. This could be taken orally.Preferably, it would be taken mucosally. Acute Alzheimer's Disease couldbe treated by parenteral injection. Alternately, a mixture of hyaluronicacid and chondroitin sulfate could be administered daily for preventionor treatment of Alzheimer's Disease. Again, the daily dose wouldpreferably be less than a total of 100 mg.

The significant neurological degeneration that occurs after spinal cordinjuries leading to irreparable paralysis, is attack by the leukocytesrushing to the site of trauma (via the mechanism of the adhesioncascade) to help repair the traumatized area, but instead, degrading theends of the nerves in the spinal cord, fraying them which effectivelyinhibits their potential realignment and partial or complete repair.Paralysis resulting from spinal cord injuries may be prevented ortreated effectively using the complex carbohydrates of this invention.In this case, since the patient may not be able to take an oralmedication, the medication may be administered mucosally usingsuppositories (rectal or vaginal) or parenterally, injecting IM, SC, ordelivering IV. The dose may need to be higher, in the range of 20 to1,000 mg per day. Drugs to assist repair of nerves would preferably beadministered concurrently.

The invention is further illustrated but is not intended to be limitedby the following examples.

Example 1

An 18 year old female suffered from chronic fibromyalgia localized inthe face and neck. This condition had existed for approximately 5 years.There was nothing that provided relief for her condition. Prior to useof the compositions of the present invention, she had taken painrelievers, acupuncture, and numerous other procedures to treat hercondition. Nothing had provided substantial relief without severe sideeffects. She was given a formulation containing a mixture of high andlow molecular weight 1% sodium hyaluronate. This formulation wasprepared from hyaluronic acid powder obtained from CollaborativeLaboratories, Inc. which was made up to a 1% solution in deionized,distilled water. One half of the final 1% solution was removed and itsmolecular weight was broken down by alkaline hydrolysis. The pH wasadjusted to between 11 and 14 using 10N NaOH. Then the solution washeated while mixing at a temperature between 37° and 50° C. When amolecular weight of between 10,000 and 50,000 was obtained as measuredby viscosity (Brookfield Viscometer), the pH was adjusted back toneutral (between 6.0 and 7.0). The final mixture was then prepared bycombining 1 liter of this low molecular weight preparation with 1 literof the original 1% solution (high molecular weight of >1×10⁶) of sodiumhyaluronate. The patient was instructed to take this formulation orally,holding the liquid in the mouth for several seconds to allow mucosaladsorption before swallowing it. She took 10 mg two times per day (AMand PM). This represented a dose of approximately 0.2 mg/Kg. Shereported that after only 1 day, her symptoms were greatly improved.After one week of daily use, she reported essentially no pain. She hascontinued to take the same dose for 6 months and has reported no returnof her fibromyalgia as long as she takes the formulation. Therefore, acondition that has historically remained untreatable, and which appearsto be related to the adhesion cascade and, perhaps, to allergies hasbeen shown to be treatable with the compositions of the presentinvention.

Example 2

A 9 year old male suffering from severe Attention Deficit HyperactivityDisorder (ADHD) complicated by Turret's Syndrome, who was being treatedby diet control with little success, was given a sample of the mixtureused in EXAMPLE 1. This treatment was not complicated by concurrenttreatment with drugs such as Ritalin as his parents were adverse tousing this medication. Therefore, any response observed was related tothe use of the complex carbohydrates of the present invention. He took10 mg in the morning and 10 mg in the evening, using the solution as amouthwash (holding it in his mouth for about 10 to 20 seconds and thenswallowing). His parents kept very strict records of his activity andnoted that his Turret's Syndrome was fully controlled and he suffered notics while taking the sodium hyaluronate. The one day that he forgot totake his morning dose he had a recurrence of his tics and became almostuncontrollable. However, within 15 minutes of his receiving the missingdose, he became calm and returned to normal. This boy has remainedtotally under control for 6 months. This had never been observed before,even when he was taking Ritalin. He had discontinued taking Ritalin 1.5year before because of problems with side effects. The sodiumhyaluronate provided no adverse reactions or side effects. It has beenconcluded that a disease typically thought to be related to a nervousdisorder or to allergies was treatable by the complex carbohydrates ofthe present invention.

Example 3

A 60 year old male and 55 year old female (brother and sister) whoroutinely suffered severe sunburns the first few times that they were inthe sun each summer, had been taking oral sodium hyaluronate gel fortreatment of pain associated with a cervical disc stenosis (male) andchronic osteoarthritis of both knees (female). Pain from the conditionsbeing treated was totally controlled by taking 5-10 mg twice per day.This dose represented 0.14 and 0.18 mg/Kg respectively. The sodiumhyaluronate gel was prepared by adding sodium hyaluronate (CollaborativeLaboratories, Inc) to deionized, distilled water to a 1% concentration.Preservatives selected from methyl paraben (0.17%), propylparaben(0.025%) and propylene glycol (10%) were added to maintain sterility ofthe liquid preparation. The pH of this preparation was between 6 and 8and the preparation had a molecular weight of >1,000,000. The gel wasbeing applied directly on the tongue by dropper bottle. Both went onvacation together and spent most of 5 days in the bright sun in a boat.They did not use a sun blocker. Each previous year both had sufferedsevere discomfort from sunburn after the first day's exposure. Thistime, at the end of the 5 days, both noted that they were not sunburned,had suffered no discomfort and were developing a nice tan. It isconcluded that the preparation of this invention prevented sunburn,allowing tanning to occur. Additionally, it was noted that theformulation of this invention was able to control the pain associatedwith cervical disc degeneration and osteoarthritis. All such conditionsare associated with the adhesion cascade, confirming that diseases andconditions associated therewith are preventable or treatable by thecomplex carbohydrates of the present invention.

Example 4

A 60 year old male suffering from colon cancer had been unable totolerate his colostomy and demanded that his surgeon remove thecolostomy and reconnect his colon. He refused chemotherapy. He was givena formulation of 1% sodium hyaluronate (Collaborative Laboratories, Inc)which was prepared with a mixture of molecular weights of hyaluronate(as described in EXAMPLE 1). When he began taking the hyaluronatepreparation, his CEA was 70.1. He has taken the hyaluronate at a dose of10 mg three times per day mucosally and after 6 months of treatment hisCEA has dropped to 4.1. He has taken no other treatments. This patienthad also suffered from polymyositis for approximately 15 years. For thiscondition he was taking 50 mg of Prednisone daily with little relief. Hereported that after 1 week of taking the hyaluronate preparation of thepresent invention, he felt significant relief from the pain caused byhis polymyositis. After 6 months of treatment with hyaluronate, he hasbeen able to reduce his Prednisone to 5 mg every other day. Hisphysician has reported that his polymyositis has gone into remission.This treatment of cancer demonstrates the successful use of the complexcarbohydrates of the present invention to treat a disease associatedwith the metatastic cascade. The polymyositis that was successfullytreated in this example was thought to represent treatment of a diseaseassociated with the adhesion cascade or autoimmune disease.

Example 5

The subject adult was a 48 year old female who had suffered all her lifewith attention deficit disorder (ADD).

She never knew what her problem was until recently when she wasdiagnosed. She described her childhood as unfocused and explained thatshe felt as though she was in a constant mental fog—unable to thinkclearly, or for that matter, unable to focus on a thought at all. Shefound that she had allergies to almost everything including most foods(dairy products, wheat and corn, sugar, corn syrup, etc.) and mostenvironmental inhalants, the worst being mold. Exposure to only a fewminutes in a moldy room caused this individual to become dazed, unableto think, focus or even stay awake. She had only been able to do menialjobs. She spent most of her time staring out the window with no thoughtsin her mind and, even if she tried, could not focus on a thought ortask. She described herself as believing all her life that she was juststupid and unable to learn. She had been to multiple physicians andpsychiatrists seeking treatment with no success. She had taken Ritalinwith little relief. It allowed her to function partially but she wasalways tired and unable to focus on anything but the simplest of tasks.She agreed to take the oral sodium hyaluronate product and her familywould report how she reacted. She did not believe that she could recordher own responses because she was unable to concentrate long enough forsuch a task. She was initially provided low molecular weight sodiumhyaluronate (<30,000), prepared as described in EXAMPLE 1. She began bytaking 20 mg 3 to 4 times per day. Within five days of the start oftreatment, she reported that she could focus enough to write a noteabout how she felt each day. As she was on the instant compositionlonger, her notes became more coherent and within about 10 days she wasable to determine exactly which foods caused her the most problems andwhich environmental exposures caused the major difficulty. Shediscovered that various types of foods were actually producing her“mental fog” reaction, an anger reaction, welts on her face and neck andeven anaphylaxis. After 30 days of taking the sodium hyaluronate oralformulation, she described her response as follows: “Before starting theoral formulation, I was in a continual state of feeling tired, foggy,feeling cold, having rashes and welts all over, and having a ‘tighthead’. I couldn't function well enough to drive or hold any type of job.I now believe that I know what a normal person must feel like. I'mhaving longer periods of well being, energy and clear thinking. Eachweek I have seen a progression of positive responses. This is the firsttime I have been able to define periods of allergic reaction. I canobserve when reactions start and end. I'm not using nasal spray(Flonase) in the morning when I wake up or, especially before I go tobed. Before starting the oral formulation, I had to use this spraybefore bedtime or I would wake up in the middle of the night, coughingand choking with a lot of phlegm. I am able to start and finishprojects. I have even been able to work crossword puzzles—something thatI could never even look at prior to treatment. My quality of life is farsuperior than ever before. I have been offered a real job at anadvertising agency. I feel like I can handle the job and do not getfrustrated and spacey. I am also able to drive a car—something that Ihaven't done for at least 15 years.”

FIG. 1 plots the response of this patient while taking the compositionsof the present invention. It is based on the patient's own descriptionof her average daily activities and reactions. The scale runs from a −30(a reaction in which the patient responded in a manner wherein she wasunable to function or focus on any activity) to +30 (energy,clear-thinking, able to focus, feel great). If there were no significantnegative or positive responses during a day, the reaction rate wasrecorded as 0. The graph clearly demonstrates that the oralglycosaminoglycan (sodium hyaluronate) improved this patient's qualityof life and reduced the reactions (after eating or exposure toenvironmental reactants). Toward the latter part of treatment, thispatient was provided with a high molecular weight (>1,000.000) oralhyaluronate formulation. Her family reported an immediate lack ofresponse that continued during the time when she continued to take thisformulation. She was unable to work or drive a car during this period oftime. After 9 days on the high molecular weight formulation she wasswitched to a formulation that contained a mixture of molecular weightsof hyaluronate (as described in EXAMPLE 1). This formulation wasprepared by mixing 3 parts of low molecular weight (<30,000) with 1 partof high molecular weight (>1,000,000). She demonstrated an immediatepositive response that has continued. She has reported that whereaswhile taking the low molecular weight hyaluronate she felt extremelyenergetic and capable of doing anything and everything, when she ate orwas exposed to something that caused her significant problems, shesuffered from extreme “crashes”. These “crashes” were observed by theinventor and would be described as a catatonic state in which thispatient did not respond. She sat and stared into space or fell asleep.While taking the mixed molecular weight hyaluronate, she was notexperiencing “highs” or “crashes”. Instead, she maintained a feeling offocus, felt good and was capable of completing her work and family tasksas she thought a normal person would do. As can be observed in the graphin FIG. 1, when the low molecular weight sodium hyaluronate was replacedwith high molecular weight sodium hyaluronate (without the patient'sknowledge) the patient reported a total lack of efficacy. When she wasplaced back on the mixed molecular weight preparation, she returned to astate where she was functioning well, had excess energy and was able tofocus. This individual has now periodically replaced the sodiumhyaluronate with liquid 5% chondroitin sulfate. The positive responsecontinued while taking this low dose chondroitin sulfate.

Example 6

The patient from EXAMPLE 5 did experience 2 anaphylactic reactions aftereating certain foods containing corn syrup or being exposed to mold.During such reactions she would become catatonic and collapse. After thefirst such reaction, a pharmaceutical grade low molecular weight sodiumhyaluronate (approximately 350,000 MW) was administered intramuscularly.She was observed for her response. Within 10 minutes she becameconscious and was able to speak haltingly. She was unable to focus wellon the conversation. Within 30 minutes she appeared normal and was ableto carry on a coherent, intelligent conversation. She had no idea whathad happened.

When a similar anaphylactic reaction occurred at a later date, it wasdecided to treat with oral hyaluronate. She again was catatonic andunconscious. Approximately 1 mL of low molecular weight (<30,000) sodiumhyaluronate was applied under her tongue and around her gums. Thistreatment brought an initial response of consciousness within 30minutes. Halting speech without the ability to focus occurred by 45minutes post treatment. By 60 minutes post treatment she was able tocarry on a focused conversation and appeared normal. This demonstratesthat a glycosaminoglycan such as hyaluronate can be used to treatanaphylaxis when administered either parenterally or orally/mucosally.

Example 7

The subject child was a 9 year old male who has suffered with ADHD allhis life. He had demonstrated learning disabilities compounded withbehavioral problems. He was described as unable to focus, did not read,write or draw. Additionally, his behavior was such that he could notsocialize with other children or with adults. When in contact with otherchildren he was unable to play, often became angered and caused physicalharm to others. He had been under treatment by several physicians,psychologists and allergists all his life but none were able to help hiscondition. The allergists determined that he had allergies to most allfoods, dust, molds, soaps and just about everything in his environment.At one time he was prescribed Ritalin daily. However, while taking thisdrug he suffered hallucinations and became even more uncontrollable. Atthe time that he began treatment according to the present invention, thephysician who was treating him was convinced that his ADHD was relatedto his severe allergies. Eating a certain food, such as corn,immediately produced anger and rage in this child. Similar responseswere noted after eating or being exposed to other foods or mold.

This boy attended a special school in which his Teachers reported hisdaily activity to his parents so that they could try to monitor hiseating habits. They provided a daily numerical score. A score of 100 wasexcellent. This child averaged daily scores of 0 to 10, at best. Thischild was placed on the low molecular weight oral glycosaminoglycan,sodium hyaluronate. A dose of 20-30 mg BID was applied orally in food ordrinks. It was added to rice milk for breakfast and made into icing forcookies for snacks as he was not cooperative enough to take it on hisown. His response was monitored by using the numerical score provided byhis teachers and averaging it with a numerical score of his behavior athome provided by his parents. The child responded positively within afew days. The average scores plotted in FIG. 2, ranged from −40 to +40.Normal non-aggressive behavior was given a score of 0. The teachers atschool were not informed of this treatment. Within 5 days of beginningtreatment the comments from his teachers were: “He appears happy, havinga good time but needs direction. Awesome day. Plays well withclassmates. Helps other children who are having problems”. His parentshave commented that he has awakened in the morning and is happy,cheerful and cooperative in getting ready for school. This is somethingthat they had not experienced in the past. He has suffered no adversereactions from taking the complex carbohydrates of the presentinvention. FIG. 2 shows the response of this child to oral low molecularweight hyaluronic acid. The y axis is a numerical analysis of thischild's ability to cooperate with other children and adults. If hisbehavior was belligerent, bossy, angry or non-cooperative he was scoredas a −40 for the day. If his reactions to foods or environmental stimuliproduced such a response it was recorded as a −40. If he responded as anormal 9 year old, the score was recorded as 0. If he respondedextraordinarily well, helping other children, reading quietly, drawingor writing, he was given a score of +40. It was quite surprising thatthis child responded almost immediately becoming “a different child”.His parents had thought that he did not know how to read, write or draw.Almost automatically, he requested books from the library and beganreading quietly, he began drawing very intricate drawings and writingpoems and stories. He also began preparing very elaborate meals for hisparents (without any assistance). FIG. 2 demonstrates this superiorbehavior quite well. It also demonstrates that when treatment wasstopped for approximately 2 weeks, there was a reversion to his originalnon-cooperative behavior. Upon restarting the treatment his behaviorimproved dramatically. It is thus clear that the glycosaminoglycans ofthe present invention can treat ADHD very effectively. Any route ofadministration may produce similar effects. In the most severe cases,the treatment would begin with a parenteral injection followed by oralor mucosal daily doses.

Example 8

The patient was a 37 year old female who had suffered from interstitialcystitis for eight years. She had seen many doctors and been to MayoClinic to seek treatment that could provide her with relief. Thiscondition presents as a constant pain in the bladder that produces“excruciating pain” and a sensation of an intense need to urinate(urgency). It appears to be caused by inflammation of the lining of thebladder. Cysts or sores develop that are irritated by the urine in thebladder. Since the bladder cannot empty, there is constant irritationand constant pain. A recent theory is that the irritation is produced byallergic reactions to certain foods or drinks and by sexual intercourse.This patient had been to all types of physicians and even to the MayoClinic to obtain relief from her pain. She had been taking 100 mg perday of macrodantin and 20 mg per day of feldene that caused severe sideeffects. Additionally, she had taken 200 mg TID of Elmiron to reduce theinflammation in the bladder lining. This did not help. In order to sleepshe took Prosed/DS, Ultram, Hydroxyzine HCl, Cardura, Amitriptyline.Sometimes all were taken at some time during the day or night. Even thisregimen was unable to treat the pain. This patient was supplied with themixed molecular weight preparation of sodium hyaluronate as described inEXAMPLE 1. She was also supplied with a topical preparation containing1% wt/vol. Sodium hyaluronate at a molecular weight of <30,000 combinedwith 1% Oil of Wintergreen, 0.5% Spearmint Oil and 0.2% Peppermint Oil.She took 10 mg of the oral preparation 4 times per day. The last dosewas taken before going to bed. Additionally, at bedtime, she rubbed herlower abdomen (over the bladder) with the topical preparation. Shereported that she was able to sleep at least 6-7 hours without pain andwithout the need to get up to urinate. Within a week after starting thistreatment she was able to discontinue all other medications. Now, allshe requires is 1-2 Tylenol plus the sodium hyaluronate preparation ofthe present invention and she has continued to remain pain free. Thisdemonstrates that inflammation, even in the bladder where the sodiumhyaluronate does not penetrate, can be successfully treated with thecompositions of the present invention. The additional fact that thetopical preparation provided “an extra bonus of immediate relief”indicates that the topical use of the compositions of the presentinvention are extremely effective in treating extreme pain. It isproposed that the allergic reactions that stimulate this condition weresuccessfully treated to relieve the constant irritation of the bladder.

Example 9

A 49 year old female who was diagnosed with Lupus Erythematosis 24 yearsago, presented with an acute outbreak of the disease. Her face wascovered with eruptions as was the skin on her forearms. She was alsofeeling very tired and complained of general joint pain. She wasprovided with a sodium hyaluronate preparation with a molecular weightof <30,000. She was instructed to initially take 10 to 20 mg of theliquid TID. She reported that after taking the first dose, the eruptionson her face began “drying up”. By the third dose the eruptions weresignificantly reduced and beginning to heal. Within 3 days, theeruptions had essentially disappeared. This patient has been treatedwith the composition of the present invention for a period of 8 monthswithout a recrudescence of the disease. She also reported that theconstant aching and pain in her joints had disappeared and she felt 100%improvement.

Lupus Erythematosis is known to be an autoimmune disease. Therefore, thecomplex carbohydrate compositions of the present are able tosuccessfully treat said autoimmune disease.

Example 10

An 80 years old female had been diagnosed with ovarian cancer that hadspread to the lungs, liver and spleen. She refused chemotherapy. She wastold that she had 3 weeks at most to live. She was provided treatmentwith the complex carbohydrate compositions of the present invention.When first provided with oral/mucosal sodium hyaluronate of mixedmolecular weights (prepared according to the methods described inEXAMPLE 1), she had not eaten in 6 months and was unable to keepanything down, she was in extreme discomfort from extensive build up offluids in the abdomen and chest and pain in the legs and feet which wereextremely swollen. She was on an IV solution to restore fluids since shecould not drink liquids. She was instructed to place as much as possibleof the oral preparation in her mouth and let it absorb under her tongue.This was to be repeated as often as possible. Within 2 weeks she wasable to eat small amounts of food. At this time, she received injectionsof 10 mg doses of sodium hyaluronate three times per week. Her conditioncontinued to improve. As of this writing, she continues to improve, eatsbetter each day and has survived for 4 months. She has received nochemotherapy and no other treatments. She indicates that she feelsstronger each day and has been able to begin sitting in a chair andstanding up. She has indicated that she has no pain since beginning totake the oral complex carbohydrates of the present invention. Thisdemonstrates that even a terminal cancer patient who was near death canrespond to treatment with the complex carbohydrate compositions of thepresent invention.

Example 11

A 38 year old male had suffered from high blood pressure most of hisadult life. He had tried taking numerous drugs to treat his conditionwith little to no success. He agreed to try a complex carbohydrate ofthis invention to determine whether it might have a positive effect. Hewas supplied with a 1% solution of sodium hyaluronate formulation with amolecular weight range between 10,000 and 50,000. He took 10 mg in themorning and 10 mg in the evening. Sometimes he supplemented with a 10 mgdose after lunch if he was having a particularly stressful day. Thepatient's weight was 163 lbs. Therefore, each dose was 0.06 mg/Kg. Table1 shows the results. The patient's blood pressure ranged around 160/115prior to treatment. Within three days of starting treatment his bloodpressure was dropping. By one week post initiation of treatment, hisblood pressure was within the normal range. It has remained well withinthe normal range for six months during treatment with the complexcarbohydrates of this invention. It is evident that high blood pressurecan be effectively treated with the complex carbohydrate formulations ofthe present invention.

TABLE 1 Treatment of High Blood Pressure with Sodium Hyaluronate BP 5min BP 1 hours BP 2 hours BP Prior to Post post post Day medicationmedication medication medication −3 168/121 N/A N/A N/A −2 166/119 N/AN/A N/A −1 169/121 N/A N/A N/A 0 167/119 N/A N/A N/A 1 166/114 160/100142/98 140/88 2 160/100 154/110 150/104 141/89 3 158/90 154/100 143/89144/89 4 148/98 144/99 140/89 139/85 5 149/99 143/87 140/80 139/78 6150/87 145/89 139/85 138/77 7 146/86 144/89 135/78 136/79 8 139/78136/87 135/78 139/81 9 135/85 136/76 133/79 139/78 10 138/87 133/77134/77 133/78 11 137/76 139/88 138/79 141/87 12 137/88 137/89 134/80135/77 13 136/77 136/78 133/76 134/75 14 137/79 134/81 133/75 133/75 15138/77 133/76 132/78 135/74 16 133/74 133/77 134/77 132/68 17 140/78139/76 133/76 133/77 18 133/76  8/78  32/75 133/78 19 135/75 131/73131/75 133/74 20 133/76 131/74 133/73 132/76 30 134/74 135/76 134/71135/74 180 133/78 135/78 136/73 133/72 BP = Blood Pressure

Example 12

An eleven year old Labrador retriever had suffered from lick granulomasfor at least 3 years. This condition of dogs are reportedly caused bynervousness wherein the dog continues to lick a certain site until anopen wound is produced. Licking is continued and the open wound becomessignificantly irritated and swollen. This dog's granuloma was located onthe left hind leg above the pasturn. The swelling around the legmeasured 8 inches in diameter and the open wound measured 4×3 inches.The dog had been treated with cortisone injections and hydrocortisonecreams with little success. This dog was injected with 10 mg of sodiumhyaluronate having a molecular weight ranging from 30,000 to 400,000(1.0 mL intramuscularly—equivalent to 10 mg). The open wound began toheal. This injection was followed up with topical application of a lowmolecular weight hyaluronic acid prepared by making a 1% (wt/vol)solution of hyaluronic acid (Medex Ltd) containing 1% Wintergreen Oil(Loranne Oil), 1% Spearmint Oil (Loranne Oil) and 0.5% Peppermint Oil(Loranne Oil). The topical formulation was applied at least two timesper day. Over a period of 2 months the lick granuloma healed completelyand the swelling reduced to a diameter of 3 inches. The dog has notlicked this area since treatment began. Therefore, the complexcarbohydrates of the present invention are able to successfully treatlick granulomas (a previously untreatable condition of dogs) andeliminate the cause of the licking.

Example 13

Dogs often develop areas on their skin that become irritated and thatthey lick until the area is raw and oozing. Often these areas becomeinfected with normal flora (bacteria) on the skin. Additionally, thehair around the area is usually either licked off or sloughs off. Theseareas are termed “hot spots”. They are extremely difficult to treat andare thought to be caused by allergies to foods or environmental stimuli.Treatment generally includes cortisone by injection or by mouth followedby antibiotics (oral or topical) to treat the complication of bacterialinfection. Three dogs with severe hot spots were treated with thecomplex carbohydrates of the present invention. Dog #1 had a large hotspot on the top of the head (diameter 3×2 inches) and smaller onesaround the muzzle area. Dog #2 had a large hot spot on its back just infront of the tail.

This area measured approximately 6 inches in diameter. Dog #3 had hotspots down the back of both hind legs and on the groin area of both hindlegs. Parenteral sodium hyaluronate was administered to Dog #1. This dogreceived 3×10 mg doses at one week intervals. The hot spot on dog #2 wastreated with topical sodium hyaluronate. The formulation was the same asthat described in EXAMPLE 15. The topical formulation was applied BIDdirectly on the hot spot. Dog #3 received sodium hyaluronateadministered orally. This dog received 5 mg BID on its food.

Hot Spots: Reports on the treatment progress were made by the owners andare shown in Table 2. Table 2 indicates that all of the treatments wereeffective. It appears that the parenterally administered sodiumhyaluronate was slightly more effective than the orally or topicallyadministered product. However, all were more effective than the previoustreatments used. Additionally, none of the dogs have had recurrent hotspots, even one year after the initial treatment.

TABLE 2 Response of Dogs with Hot Spots to Treatment with SodiumHyaluronate Days Post Treatment Initiation Dog #1 Dog #2 Dog #3 1 NC NCNC 2 Dog Quit Licking NC Dog Quit Licking 3 Drying Dog Quit LickingDrying 4 Same Same Same 5 Healing Well Drying Healing Well 6 Same SameSame 7 Same Same Same 8 Significantly Healing Well Significantlyimproved Improved 9 Same Same Same 10 Same Significantly Same Improved11 Size now 1 inch Same Same in diameter 12 Same Size now 2 Size now 1inch inches in in diameter diameter 13 Essentially Same Same healed 14Same Size now 1 inch Essentially in diameter healed 15 Hair growingEssentially Hair growing back healed back 16 Hair growing Hair growingHair growing back back back 17 Same Same Same 18 Same Same Same 19 SameSame Same 20 Completely Can still see a Hair almost healed slight lesiongrown back 21 No new lesions Same Same 22 Same Completely Completelyhealed healed 23 Same Same Same 24 Same Same Same 25 Same Same Same 26Same Same Same 27 Same Same Same 28 Same Same Same 29 Same Same Same NC= No Change

Example 14

An 83 year old female suffered from chronic eczema—scaly and red areason her neck and arms. She had also been diagnosed with a yeast infectionassociated with the eczema. She had tried all types of treatments,including cortisone with no significant effect. She initially used atopical preparation prepared according to this invention. This containeda mixture of low and high molecular weight sodium hyaluronate (preparedas in EXAMPLE 1) mixed with 1% Wintergreen Oil, 1% Spearmint Oil, and0.5% Peppermint Oil. She applied it topically for four weeks. She notedthat the bright redness of the eczema subsided. However, there was stillitching and redness. She then began to orally take the 1% mixture, oflow and high molecular weight sodium hyaluronate described in example 1.She reported that within 2 weeks all signs of the eczema haddisappeared, the itching was gone and she felt better than she had feltfor years. The oral dose required was 5 mg TID for this 91 pound female.Therefore, the dose was 0.05 mg/Kg. This demonstrates that the complexcarbohydrates of the present invention is effective in treating severecases of eczema even when they are complicated with a yeast infection.

Example 15

In order to determine whether low doses of other complex carbohydratestaken orally or mucosally could show effects similar to hyaluronic acid,3 patients presenting with Lupus Erythematosis, interstitial cystitisand high blood pressure were treated with oral liquid chondroitinsulfate. None of these patients had taken chondroitin sulfatepreviously. A 5% (wt/vol) solution of chondroitin sulfate (InfinityLaboratories, Inc) without essential oils was prepared. This wasdispensed into 30 ml bottles and provided to the three patients withinstructions to take 1.0 mL orally BID, holding it in the mouth forapproximately 10 seconds prior to swallowing it. This represented a doseof 5 mg BID. The weight of the two patients were 155 lbs and 128 lbs,respectively. Therefore, the doses administered were 0.07 mg/Kg and 0.09mg/Kg. This provided relief (within 15 minutes). However, the relieflasted only 1-3 hours. The patients reported that they had to take thechondroitin Sulfate solution three to five times per day to obtainsuccessful treatment. After two months of this regimen, the patientswere given a mixture of the 5% chondroitin sulfate and 1% high molecularweight hyaluronic acid. They were instructed to take this as often asnecessary. Each reported that this product was effective when taken only2 times per day and the effect lasted from 8 to 10 hours for the Lupuspatient and for the interstitial cystitis patient. This demonstratesthat a mixture of low and high molecular weight complex carbohydrates ismore effective and that significantly lower doses (100 to 1000 fold lessthan currently suggested for OTC use) of chondroitin sulfate arerequired for more effective treatment of Lupus Erythematosis,interstitial cystitis and high blood pressure. Chondroitin sulfate iswidely known and used in tablets for arthritis. However, it is used forsuch treatment at very high doses (greater than 1000 mg per day). Wehave found that very low concentrations when administered in liquid formorally, mucosally or topically, is more effective than the higher dosesin a powder form. Additionally, the inventors are not aware of any useof chondroitin sulfate for any of our other indications of thetreatments and diseases listed.

Example 16

A 55 year old female and a 56 year old male felt that they were comingdown with a cold. Both had oral sodium hyaluronate prepared as describedin EXAMPLE 1 available to them and began taking a 3 to 5 mg dose orallyevery 3 to 4 hours. They commented that the pain of the sore throat wasgone within 15 minutes of taking the oral preparation. Additionally, thecold seemed to be very mild and quickly progressed through the normalstages, each stage being much milder than normal for these individuals.The female reported that her cold lasted only 4 days as compared withher historical colds that lasted 21 to 24 days. The male reported thathe seldom noticed the symptoms of his cold and felt fine in 3 to 4 days.Historically, his colds lasted approximately 14 days. These resultsindicate that the complex carbohydrates of the present invention reducethe symptoms of colds and that they have anti-viral activity.

Example 17

In order to determine whether scar tissue could be reduced byapplication of the complex carbohydrates of the present invention.Sodium hyaluronate having a molecular weight range of between 10,000 and2 million was formulated so that it could be used as a scar reductionpatch. The formulation was prepared as follows: To 50 mL of 1% sodiumhyaluronate (Medex Ltd) was added 7 grams of alphy-hydroxy acid. Thesolution was mixed until a clear solution was produced. Then 20 mL ofUSP Glycerol was added and this was mixed to homogeniety. Finally, 1%sodium hyaluronate was added to QS the volume to a total of 100 mL.After the final HA addition, the solution thickened and was spreadevenly on the bottom of a petri dish. It was allowed to dry for 48 hoursat room temperature after which it was used to treat a fresh scarproduced as a result of reconstructive surgery on the left hand of a 50year old female patient. The solidified HA was cut into a shape slightlylarger than the scar. It was applied over the scar and held in place byapplying an ace bandage. Approximately ½ of the scar was left untreatedso as to serve as a control. The Bandage was allowed to remain over thescar for a period of 2 weeks. Intermittently, the HA patch was removedand the scar was cleaned. If the solidified HA patch dried out, it wasmoistened slightly with water and reapplied. After only two weeks ofapplication the raised scar tissue (adhesion) had essentiallydisappeared. This demonstrates that scar reduction can be accomplishedby use of the complex carbohydrates of the present invention.

Example 18

In order to determine whether open wounds could be stimulated to healfaster, gauze was soaked in 1% sodium hyaluronate having a molecularweight range from 30,000 to 500,000 and allowed to dry. ThisHA-containing gauze was applied to open wounds of the followingtypes: 1) a rug burn produced by sliding on artificial turf on afootball field; 2) a surgical wound resulting from a hip replacement;and 3) a cut finger resulting from a piece of broken glass. The bandageswere kept on the wounds until they were healed well enough to remainuncovered. It was reported that the rug burn was healed within 3 days.This compared with a 2 week healing period normally experienced by thispatient. The surgical wound healed within 5 days, again almost 10 dayssooner than expected. The cut finger was healed within 3 days. Theconclusion was that a glycosaminoglycan is very effective in stimulatingwound healing when incorporated into gauze and used as a bandage.

Example 19

Ten patients taking oral preparations of 1% sodium hyaluronate (1 takinglow molecular weight ranging (from 10,000 to 300,000), 4 taking mediummolecular weight (ranging from 100,000 to 600,000), and 5 taking highmolecular weight (ranging from 500,000 to 2 million), reportedseparately that they had noticed the following positive effects inaddition to the treatment effects for which they were taking the complexcarbohydrate. They were impressed in the increased cognitive effectsthat they noticed. They reported that their memory had significantlyimproved as had their ability to focus on information and tasks(cognitive function). Additionally, each reported that they experiencedthickening of their hair and fingernails as well as improvement in theirskin condition (their skin was more supple and the wrinkles in theirface were reduced). These effects resulted directly from the use of thecomplex carbohydrates of the present invention.

Example 20

Four of the patients taking oral or mucosal complex carbohydrates (1taking 5% chondroitin sulfate and three taking 1% sodium hyaluronatewith a molecular weight range from 30,000 to 500,000) have reportedthat, prior to taking the complex carbohydrates of the presentinvention, they had been plagued with repeated vaginal yeast infections.All had been suffering from yeast infections at the initiation of thepresent treatment. They were not taking other medications to treat theseyeast infections. All four patients reported that their yeast infectionsdisappeared within 3 to 7 days of beginning treatment with the complexcarbohydrates of the present invention. They have remained on thepresent treatments for approximately 14 months and have remained yeastinfection free. It is concluded that the complex carbohydrates of thepresent invention are able to treat and/or prevent yeast infections.

All cited patents, provisional applications, publications and PCTapplications referred to in this application are herein incorporated byreference.

Although the invention has been described in detail in the foregoing,for the purpose of illustration it is to be understood that such detailis solely for that purpose and that variations can be made therein bythose skilled in the art without departing from the spirit and scope ofthe invention except as it may be limited by the claims.

1. A method of treating at least one inflammation-based disease orcondition selected from the group consisting of autism, AttentionDeficit Disorder, Turret's Syndrome, anaphylaxis, fibromyalgia andinterstitial cystitis, allergies, asthma and emphasema comprisingadministering hyaluronic acid or a salt thereof wherein the hyaluronicacid or salt thereof comprises at least one fraction having a molecularweight of greater than 1,000,000 daltons and wherein hyaluronic acid orsalt thereof is administered orally or mucosally.
 2. The methodaccording to claim 1, wherein the hyaluronic aid or salt thereof isadministered parenterally.
 3. The method according to claim 1, whereinthe composition is administered with at least one transmucosal carrierin an amount effective to treat at least one inflammation-based diseaseor condition selected from the group consisting of Attention DeficitDisorder, autism, Turret's Syndrome, anaphylaxis, fibromyalgia andinterstitial cystitis.
 4. The method according to claim 1, wherein thehyaluronic acid or salt thereof is of low purity such that it wouldproduce an inflammatory response in an owl monkey eye test but would notproduce an adverse reaction when applied to the skin or mucous membranesof mammals.